11-124885038-C-T

Position:

• chr11-124885038-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_019055.6(ROBO4):​c.3001+3G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0103 in 1,614,048 control chromosomes in the GnomAD database, including 149 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0081 (9 hom., cov: 32)
  • Exomes 𝑓: 0.010 (140 hom.)
• Consequence: ROBO4 NM_019055.6 splice_region, intron
• Scores: Splicing: ADA: 0.00003975
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.554

Genes affected

ROBO4 (HGNC:17985): (roundabout guidance receptor 4) Predicted to enable cell-cell adhesion mediator activity. Involved in angiogenesis and establishment of endothelial barrier. Located in extracellular exosome. Implicated in aortic valve disease 3. [provided by Alliance of Genome Resources, Apr 2022]

ROBO4 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 11-124885038-C-T is Benign according to our data. Variant chr11-124885038-C-T is described in ClinVar as [Benign]. Clinvar id is 2642502.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00813 (1239/152348) while in subpopulation NFE AF= 0.0124 (844/68032). AF 95% confidence interval is 0.0117. There are 9 homozygotes in gnomad4. There are 539 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1239 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ROBO4	NM_019055.6	c.3001+3G>A		splice_region_variant, intron_variant		ENST00000306534.8	NP_061928.4
ROBO4	NM_001301088.2	c.2566+3G>A		splice_region_variant, intron_variant			NP_001288017.1
ROBO4	XM_006718861.3	c.2887+3G>A		splice_region_variant, intron_variant			XP_006718924.1
ROBO4	XM_011542875.2	c.1675+3G>A		splice_region_variant, intron_variant			XP_011541177.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ROBO4	ENST00000306534.8	c.3001+3G>A		splice_region_variant, intron_variant		1	NM_019055.6	ENSP00000304945.3
ROBO4	ENST00000534407.5	n.3208+3G>A		splice_region_variant, intron_variant		1
ROBO4	ENST00000533054.5	c.2566+3G>A		splice_region_variant, intron_variant		2		ENSP00000437129.1
ENSG00000254568	ENST00000524453.1	n.673+675C>T		intron_variant		3

Frequencies

GnomAD3 genomes AF: 0.00817 AC: 1243 AN: 152230 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.00219

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.00720

Gnomad ASJ AF: 0.0300

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.00358

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0124

Gnomad OTH AF: 0.00813

GnomAD3 exomes AF: 0.00981 AC: 2465 AN: 251236 Hom.: 34 AF XY: 0.0104 AC XY: 1419 AN XY: 135802

Gnomad AFR exome AF: 0.00148

Gnomad AMR exome AF: 0.00442

Gnomad ASJ exome AF: 0.0284

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00386

Gnomad FIN exome AF: 0.00375

Gnomad NFE exome AF: 0.0150

Gnomad OTH exome AF: 0.0157

GnomAD4 exome AF: 0.0105 AC: 15314 AN: 1461700 Hom.: 140 Cov.: 32 AF XY: 0.0105 AC XY: 7621 AN XY: 727130

Gnomad4 AFR exome AF: 0.00164

Gnomad4 AMR exome AF: 0.00483

Gnomad4 ASJ exome AF: 0.0289

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00398

Gnomad4 FIN exome AF: 0.00361

Gnomad4 NFE exome AF: 0.0116

Gnomad4 OTH exome AF: 0.0116

GnomAD4 genome AF: 0.00813 AC: 1239 AN: 152348 Hom.: 9 Cov.: 32 AF XY: 0.00723 AC XY: 539 AN XY: 74506

Gnomad4 AFR AF: 0.00219

Gnomad4 AMR AF: 0.00719

Gnomad4 ASJ AF: 0.0300

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00269

Gnomad4 FIN AF: 0.00358

Gnomad4 NFE AF: 0.0124

Gnomad4 OTH AF: 0.00804

Alfa AF: 0.0116 Hom.: 7

Bravo AF: 0.00821

Asia WGS AF: 0.000867 AC: 3 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Benign, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Jan 04, 2023

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jul 01, 2024

ROBO4: BP4, BS1, BS2 -

ROBO4-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 16, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	12
DANN	Benign	0.73

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000040
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.090		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs145918924; hg19: chr11-124754934;